US9187450B2 - Substituted pyridine compound - Google Patents

Substituted pyridine compound Download PDF

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US9187450B2
US9187450B2 US13/809,115 US201113809115A US9187450B2 US 9187450 B2 US9187450 B2 US 9187450B2 US 201113809115 A US201113809115 A US 201113809115A US 9187450 B2 US9187450 B2 US 9187450B2
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group
alkyl
methyl
phenyl
dimethyl
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US20130109653A1 (en
US20140213549A9 (en
US20140005143A2 (en
Inventor
Tsuyoshi Nakamura
Hidenori Namiki
Naoki Terasaka
Akiko Shima
Masahiko Hagihara
Noriaki Iwase
Katsunori Takata
Osamu Kikuchi
Kazunari Tsuboike
Hiroyuki Setoguchi
Kenji Yoneda
Hidetoshi Sunamoto
Koji Ito
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Daiichi Sankyo Co Ltd
Ube Corp
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Daiichi Sankyo Co Ltd
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Assigned to UBE INDUSTRIES, LTD., DAIICHI SANKYO COMPANY, LIMITED reassignment UBE INDUSTRIES, LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SHIMA, AKIKO, HAGIHARA, MASAHIKO, SUNAMOTO, HIDETOSHI, ITO, KOJI, TAKATA, KATSUNORI, IWASE, NORIAKI, KIKUCHI, OSAMU, SETOGUCHI, HIROYUKI, TSUBOIKE, KAZUNARI, YONEDA, KENJI, NAMIKI, HIDENORI, TERASAKA, NAOKI, NAKAMURA, TSUYOSHI
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the present invention relates to a novel substituted pyridine compound or a pharmacologically acceptable salt thereof, which has excellent CETP inhibition activity and is useful as a medicament (particularly, a medicament for treatment or prophylaxis of dyslipidemia, low HDL cholesterolemia, arteriosclerosis or coronary heart disease).
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • CETP Cholesteryl ester transfer protein
  • Certain pyridine compounds that have CETP inhibition activity are known (for example, see Patent references 1 to 8).
  • certain pyrimidinyl piperidine compounds that have CETP inhibition activity are known (for example, see Patent references 9 to 13).
  • Patent reference 1 Japanese Patent Application Laid-Open (JP-A) No. Hei 10-067746 (corresponding U.S. Pat. No. 6,069,148 and U.S. Pat. No. 6,207,671)
  • Patent reference 2 Japanese Patent Application National Publication No. 2001-516757 (corresponding U.S. Pat. No. 6,387,929)
  • Patent reference 3 Japanese Patent Application National Publication No. 2001-517655 (corresponding U.S. Pat. No. 6,291,477, U.S. Pat. No. 6,562,976 and U.S. Pat. No. 6,897,317)
  • Patent reference 4 Japanese Patent Application National Publication No. 2005-508341 (corresponding US patent application: U.S. Application Publication No. 2005/0043341)
  • Patent reference 5 Japanese Patent Application Laid-Open (JP-A) No. Hei 10-167967 (corresponding U.S. Pat. No. 5,932,587)
  • Patent reference 6 Japanese Patent Application National Publication No. 2008-524145 (corresponding US application: U.S. Application Publication No. 2008/0255068)
  • Patent reference 7 Japanese Patent Application National Publication No. 2008-524137 (corresponding US application: U.S. Application Publication No. 2008/0194609)
  • Patent reference 8 International Publication WO2009/109549
  • Patent reference 9 Japanese Patent Application National Publication No. 2009-516649 (corresponding US application: U.S. Application Publication No. 2009/0264405)
  • Patent reference 10 International Publication WO2008/156715
  • Patent reference 11 Japanese Patent Application National Publication No. 2009-524579 (corresponding US application: U.S. Application Publication No. 2009/0023729)
  • Patent reference 12 International Publication WO2008/009435 (corresponding US application: U.S. Application Publication No. 2009/0286790)
  • Patent reference 13 International Publication WO2009/071509
  • the inventors have researched novel substituted pyridine compounds with the aim of developing an excellent CETP inhibitor and found that a substituted pyridine compound having a specific structure or a pharmacologically acceptable salt thereof has excellent CETP inhibition activity and is useful as a medicament (particularly, a medicament for treatment or prophylaxis of dyslipidemia, low HDL cholesterolemia, arteriosclerosis or coronary heart disease).
  • the invention has been accomplished on the basis of the findings described above.
  • the present invention provides a novel substituted pyridine compound which has excellent CETP inhibition activity or a pharmacologically acceptable salt thereof;
  • a pharmaceutical composition comprising a substituted pyridine compound or a pharmacologically acceptable salt thereof as an active ingredient, and a pharmaceutical composition for treatment or prophylaxis of, preferably, dyslipidemia, hypercholesterolemia, low HDL cholesterolemia, high LDL cholesterolemia, hypertriglyceridemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease (including heart failure, myocardial infarction, angina pectoris, cardiac ischemia, cardiovascular disorder and angioplasty-related restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complications) or obesity, more preferably dyslipidemia, low HDL cholesterolemia, high LDL cholesterolemia, arteriosclerosis, arteriosclerotic heart disease or coronary heart disease, further preferably dyslipidemia, low HDL cholesterolemia, arteriosclerosis or coronary heart disease, and even more preferably low HDL cholesterolemia or arteriosclerosis;
  • a substituted pyridine compound or a pharmacologically acceptable salt thereof for preparing a pharmaceutical composition for treatment or prophylaxis (preferably treatment) of diseases (preferably the above-described diseases);
  • a method of treatment or prophylaxis comprising administering to a warm-blooded animal (preferably human) a pharmaceutically effective amount of a substituted pyridine compound or a pharmacologically acceptable salt thereof; and
  • the present invention provides the following.
  • R 1 represents a hydrogen atom, a C 1 -C 6 alkyl group, a hydroxy(C 1 -C 6 alkyl) group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, a hydroxy(C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, a (C 1 -C 6 alkyl)amino-(C 1 -C 6 alkyl) group, a hydroxy(C 1 -C 6 alkyl)amino-(C 1 -C 6 alkyl) group, a [N—(C 1 -C 6 alkyl)-N-hydroxy(C 1 -C 6 alkyl)amino]-(C 1 -C 6 alkyl) group, a (C 1 -C 6 alkyl)sulfonylamino-(C 1 -C 6 alkyl) group, a [N—(C 1 -C 6 al
  • the substituent group ⁇ represents the group consisting of a C 1 -C 6 alkyl group, a hydroxy(C 1 -C 6 alkyl) group, a halogeno(C 1 -C 6 alkyl) group, a (C 3 -C 8 cycloalkyl)-(C 1 -C 6 alkyl) group, a C 3 -C 8 cycloalkyl group, a hydroxy group, a C 1 -C 6 alkoxy group, a halogeno(C 1 -C 6 alkoxy) group, a C 1 -C 6 alkylamino group, a di(C 1 -C 6 alkyl)amino group, a carboxy group, a (C 1 -C 6 alkoxy)carbonyl group, a carbamoyl group, a (C 1 -C 6 alkylamino)carbonyl group, a di(C 1 -C 6 alkyl)aminocarbonyl group,
  • R 1 is a hydrogen atom, a C 1 -C 6 alkyl group, a hydroxy(C 1 -C 6 alkyl) group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, a (C 1 -C 6 alkyl)amino-(C 1 -C 6 alkyl) group, a [N—(C 1 -C 6 alkyl)-N-hydroxy(C 1 -C 6 alkyl)amino]-(C 1 -C 6 alkyl) group, a [N—(C 1 -C 6 alkyl)-N—(C 1 -C 6 alkyl)sulfonylamino]-(C 1 -C 6 alkyl) group, a carboxy(C 1 -C 6 alkyl) group, a halogeno(C 1 -C 6 alkyl)
  • R 1 is a hydrogen atom, a C 1 -C 4 alkyl group, a hydroxy(C 1 -C 4 alkyl) group, a (C 1 -C 4 alkoxy)-(C 1 -C 4 alkyl) group, a halogeno(C 1 -C 4 alkyl) group, a C 1 -C 4 alkoxy group, a hydroxy(C 1 -C 6 alkoxy) group or a (C 1 -C 4 alkyl)sulfonyl-(C 1 -C 4 alkoxy) group.
  • R 1 is a C 1 -C 4 alkyl group, a halogeno(C 1 -C 4 alkyl) group, a C 1 -C 4 alkoxy group or a hydroxy(C 1 -C 6 alkoxy) group.
  • (6A) The compound according to (2A) or a pharmacologically acceptable salt thereof, wherein R 1 is a C 1 -C 4 alkyl group.
  • R 1 is a substituted phenyl group in which the substituent(s) represent 1 to 4 groups independently selected from the substituent group ⁇ 1, a substituted 5- or 6-membered aromatic heterocyclyl group in which the substituent(s) represent 1 to 4 groups independently selected from the substituent group ⁇ 1, a 5- or 6-membered saturated heterocyclyl group, a substituted 5- or 6-membered saturated heterocyclyl group in which the substituent(s) represent 1 to 4 groups independently selected from the substituent group ⁇ 1, a substituted 5- or 6-membered saturated heterocyclyloxy group in which the substituent(s) represent 1 to 4 groups independently selected from the substituent group ⁇ 1 or a 5- or 6-membered saturated heterocyclylcarbonyl group, and
  • the substituent group ⁇ 1 represents the group consisting of a C 1 -C 6 alkyl group, a hydroxy group, a carboxy group and an oxo group.
  • R 1 is a 5- or 6-membered nitrogen-containing saturated heterocyclyl group, a substituted 5- or 6-membered nitrogen-containing saturated heterocyclyl group in which the substituent(s) represent 1 to 4 groups independently selected from the substituent group ⁇ 2, a substituted 5- or 6-membered nitrogen-containing saturated heterocyclyloxy group in which the substituent(s) represent 1 to 4 groups independently selected from the substituent group ⁇ 2 or a 5- or 6-membered nitrogen-containing saturated heterocyclylcarbonyl group, and
  • the substituent group ⁇ 2 represents the group consisting of a C 1 -C 4 alkyl group and a hydroxy group.
  • R 1 is a substituted pyrrolidinyl group, a substituted piperazyl group, a substituted pyrrolidinyloxy group or a substituted piperidyloxy group in which the substituent(s) of the pyrrolidinyl group, piperazyl group, pyrrolidinyloxy group and piperidyloxy group represent 1 to 2 groups independently selected from the substituent group ⁇ 3, or a morpholinylcarbonyl group, and
  • the substituent group ⁇ 3 represents the group consisting of a methyl group and a hydroxy group.
  • a pharmaceutical composition comprising the compound according to any one of (1A) to (15A) or a pharmacologically acceptable salt thereof as an active ingredient.
  • a medicament for inhibiting CETP comprising the compound according to any one of (1A) to (15A) or a pharmacologically acceptable salt thereof as an active ingredient.
  • (24A) A medicament for increasing the concentration of HDL cholesterol comprising the compound according to any one of (1A) to (15A) or a pharmacologically acceptable salt thereof as an active ingredient.
  • a medicament for decreasing the concentration of LDL cholesterol comprising the compound according to any one of (1A) to (15A) or a pharmacologically acceptable salt thereof as an active ingredient.
  • (27A) The use according to (26A) for preparing a pharmaceutical composition for treatment or prophylaxis of dyslipidemia, hypercholesterolemia, low HDL cholesterolemia, high LDL cholesterolemia, hypertriglyceridemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, cerebrovascular disease, peripheral vascular disease or obesity.
  • (28A) The use according to (26A) for preparing a pharmaceutical composition for treatment or prophylaxis of dyslipidemia, low HDL cholesterolemia, arteriosclerosis or coronary heart disease.
  • (30A) The use according to (26A) for preparing a pharmaceutical composition for treatment or prophylaxis of arteriosclerosis.
  • (32A) The compound according to (31A) or a pharmacologically acceptable salt thereof, wherein the disease is dyslipidemia, hypercholesterolemia, low HDL cholesterolemia, high LDL cholesterolemia, hypertriglyceridemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, cerebrovascular disease, peripheral vascular disease or obesity.
  • (36A) A method of treatment or prophylaxis of a disease comprising administering to a warm-blooded animal a pharmacologically effective amount of the compound according to any one of (1A) to (15A) or a pharmacologically acceptable salt thereof.
  • (37A) The method according to (36A), wherein the disease is dyslipidemia, hypercholesterolemia, low HDL cholesterolemia, high LDL cholesterolemia, hypertriglyceridemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease, cerebrovascular disease, peripheral vascular disease or obesity.
  • (38A) The method according to (36A), wherein the disease is dyslipidemia, low HDL cholesterolemia, arteriosclerosis or coronary heart disease.
  • the present invention provides the following.
  • R 1 represents a hydrogen atom, a C 1 -C 6 alkyl group, a hydroxy(C 1 -C 6 alkyl) group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, a hydroxy(C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, a (C 1 -C 6 alkyl)amino-(C 1 -C 6 alkyl) group, a hydroxy(C 1 -C 6 alkyl)amino-(C 1 -C 6 alkyl) group, a [N—(C 1 -C 6 alkyl)-N-hydroxy(C 1 -C 6 alkyl)amino]-(C 1 -C 6 alkyl) group, a (C 1 -C 6 alkyl)sulfonylamino-(C 1 -C 6 alkyl) group, a [N—(C 1 -C 6 al
  • the substituent group ⁇ represents the group consisting of a C 1 -C 6 alkyl group, a hydroxy(C 1 -C 6 alkyl) group, a halogeno(C 1 -C 6 alkyl) group, a (C 3 -C 8 cycloalkyl)-(C 1 -C 6 alkyl) group, a C 3 -C 8 cycloalkyl group, a hydroxy group, a C 1 -C 6 alkoxy group, a halogeno(C 1 -C 6 alkoxy) group, a C 1 -C 6 alkylamino group, a di(C 1 -C 6 alkyl)amino group, a carboxy group, a (C 1 -C 6 alkoxy)carbonyl group, a carbamoyl group, a (C 1 -C 6 alkylamino)carbonyl group, a di(C 1 -C 6 alkyl)aminocarbonyl group,
  • R 1 is a hydrogen atom, a C 1 -C 6 alkyl group, a hydroxy(C 1 -C 6 alkyl) group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, a [N—(C 1 -C 6 alkyl)-N-hydroxy(C 1 -C 6 alkyl)amino]-(C 1 -C 6 alkyl) group, a [N—(C 1 -C 6 alkyl)-N—(C 1 -C 6 alkyl)sulfonylamino]-(C 1 -C 6 alkyl) group, a carboxy(C 1 -C 6 alkyl) group, a halogeno(C 1 -C 6 alkyl) group, a C 2 -C 6 alkenyl group, a C 3 -C 8 cycloalkyl group,
  • R 1 is a hydrogen atom, a C 1 -C 4 alkyl group, a hydroxy(C 1 -C 4 alkyl) group, a (C 1 -C 4 alkoxy)-(C 1 -C 4 alkyl) group, a halogeno(C 1 -C 4 alkyl) group, a C 1 -C 4 alkoxy group, a hydroxy(C 1 -C 6 alkoxy) group or a (C 1 -C 4 alkyl)sulfonyl-(C 1 -C 4 alkoxy) group.
  • R 1 is a C 1 -C 4 alkyl group, a halogeno(C 1 -C 4 alkyl) group, a C 1 -C 4 alkoxy group or a hydroxy(C 1 -C 6 alkoxy) group.
  • R 1 is a substituted phenyl group in which the substituent(s) represent 1 to 4 groups independently selected from the substituent group ⁇ 1, a substituted 5- or 6-membered aromatic heterocyclyl group in which the substituent(s) represent 1 to 4 groups independently selected from the substituent group ⁇ 1, a 5- or 6-membered saturated heterocyclyl group, a substituted 5- or 6-membered saturated heterocyclyl group in which the substituent(s) represent 1 to 4 groups independently selected from the substituent group ⁇ 1, a substituted 5- or 6-membered saturated heterocyclyloxy group in which the substituent(s) represent 1 to 4 groups independently selected from the substituent group ⁇ 1 or a 5- or 6-membered saturated heterocyclylcarbonyl group, and
  • the substituent group ⁇ 1 represents the group consisting of a C 1 -C 6 alkyl group, a hydroxy group, a carboxy group and an oxo group.
  • R 1 is a 5- or 6-membered nitrogen-containing saturated heterocyclyl group, a substituted 5- or 6-membered nitrogen-containing saturated heterocyclyl group in which the substituent(s) represent 1 to 4 groups independently selected from the substituent group ⁇ 2 or a substituted 5- or 6-membered nitrogen-containing saturated heterocyclyloxy group in which the substituent(s) represent 1 to 4 groups independently selected from the substituent group ⁇ 2, and
  • the substituent group ⁇ 2 represents the group consisting of a C 1 -C 4 alkyl group and a hydroxy group.
  • R 1 is a substituted pyrrolidinyl group, a substituted piperidyl group, a substituted piperazyl group, a substituted thiomorpholinyl group, a substituted pyrrolidinyloxy group or a substituted piperidyloxy group in which the substituent(s) of the pyrrolidinyl group, piperidyl group, piperazyl group, thiomorpholinyl group, pyrrolidinyloxy group and piperidyloxy group represent 1 to 2 groups independently selected from the substituent group ⁇ 3, and
  • the substituent group ⁇ 3 represents the group consisting of a methyl group and a hydroxy group.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (12) or a pharmacologically acceptable salt thereof as an active ingredient.
  • composition according to (13) for treatment or prophylaxis of dyslipidemia, low HDL cholesterolemia, arteriosclerosis or coronary heart disease The pharmaceutical composition according to (13) for treatment or prophylaxis of dyslipidemia, low HDL cholesterolemia, arteriosclerosis or coronary heart disease.
  • a medicament for inhibiting CETP comprising the compound according to any one of (1) to (12) or a pharmacologically acceptable salt thereof as an active ingredient.
  • a medicament for increasing the concentration of HDL cholesterol comprising the compound according to any one of (1) to (12) or a pharmacologically acceptable salt thereof as an active ingredient.
  • a medicament for decreasing the concentration of LDL cholesterol comprising the compound according to any one of (1) to (12) or a pharmacologically acceptable salt thereof as an active ingredient.
  • C 1 -C 6 alkyl represents straight or branched alkyl which has 1 to 6 carbon atoms and may be, for example, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 2-ethyl-1-butyl, 2,2-dimethyl-1-butyl or 2,3-dimethyl-1-butyl.
  • the C 1 -C 6 alkyl in R 1 is preferably C 2 -C 5 alkyl, and most preferably 2-propyl, 1-pentyl or 2-methyl-1-propyl.
  • the C 1 -C 6 alkyl in the substituent group ⁇ is preferably C 1 -C 4 alkyl, more preferably C 1 -C 2 alkyl, and most preferably methyl.
  • hydroxy(C 1 -C 6 alkyl) represents the above-described C 1 -C 6 alkyl substituted with 1 to 4 hydroxy groups and may be, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, dihydroxypropyl, dihydroxybutyl, dihydroxypentyl, dihydroxyhexyl, trihydroxybutyl, trihydroxypentyl, trihydroxyhexyl, tetrahydroxypentyl or tetrahydroxyhexyl, preferably hydroxy(C 1 -C 4 alkyl), more preferably hydroxy(C 1 -C 2 alkyl), and most preferably hydroxymethyl.
  • the “(C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl)” represents the above-described C 1 -C 6 alkyl substituted with one C 1 -C 6 alkoxy described below and may be, for example, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl, pentyloxymethyl, hexyloxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, methoxypentyl or methoxyhexyl, preferably (C 1 -C 4 alkoxy)-(C 1 -C 4 alkyl), more preferably (C 1 -C 4 alkoxy)-(C 1 -C 2 alkyl), and most preferably methoxymethyl, ethoxymethyl, 2-propoxymethyl or (2-methyl-1-propoxy)methyl.
  • hydroxy(C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) represents the above-described C 1 -C 6 alkyl substituted with one hydroxy(C 1 -C 6 alkoxy) described below and may be, for example, hydroxymethoxymethyl, hydroxyethoxymethyl, hydroxypropoxymethyl, hydroxybutoxymethyl, hydroxypentyloxymethyl, hydroxyhexyloxymethyl, hydroxyethoxyethyl, hydroxyethoxypropyl, hydroxyethoxybutyl, hydroxyethoxypentyl or hydroxyethoxyhexyl, preferably hydroxy(C 1 -C 4 alkoxy)-(C 1 -C 4 alkyl), and more preferably hydroxy(C 1 -C 2 alkoxy)-(C 1 -C 2 alkyl).
  • the “(C 1 -C 6 alkyl)amino-(C 1 -C 6 alkyl)” represents the above-described C 1 -C 6 alkyl substituted with one (C 1 -C 6 alkyl)amino described below and may be, for example, methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, pentylaminomethyl, hexylaminomethyl, methylaminoethyl, methylaminopropyl, methylaminobutyl, methylaminopentyl or methylaminohexyl, preferably (C 1 -C 4 alkyl)amino-(C 1 -C 4 alkyl), more preferably (C 1 -C 2 alkyl)amino-(C 1 -C 2 alkyl), and most preferably methylaminomethyl.
  • hydroxy(C 1 -C 6 alkyl)amino-(C 1 -C 6 alkyl) represents the above-described C 1 -C 6 alkyl substituted with one hydroxy(C 1 -C 6 alkyl)amino described below and may be, for example, hydroxymethylaminomethyl, hydroxyethylaminomethyl, hydroxypropylaminomethyl, hydroxybutylaminomethyl, hydroxypentylaminomethyl, hydroxyhexylaminomethyl, hydroxyethylaminoethyl, hydroxyethylaminopropyl, hydroxyethylaminobutyl, hydroxyethylaminopentyl or hydroxyethylaminohexyl, preferably hydroxy(C 1 -C 4 alkyl)amino-(C 1 -C 4 alkyl), and more preferably hydroxy(C 1 -C 2 alkyl)amino-(C 1 -C 2 alkyl).
  • N—(C 1 -C 6 alkyl)-N-hydroxy(C 1 -C 6 alkyl)amino]-(C 1 -C 6 alkyl) represents the above-described C 1 -C 6 alkyl substituted with one N—(C 1 -C 6 alkyl)-N-hydroxy(C 1 -C 6 alkyl)amino described below and may be, for example, (N-methyl-N-hydroxymethylamino)methyl, (N-methyl-N-hydroxyethylamino)methyl, (N-methyl-N-hydroxypropylamino)methyl, (N-methyl-N-hydroxybutylamino)methyl, (N-methyl-N-hydroxypentylamino)methyl, (N-methyl-N-hydroxyhexylamino)methyl, (N-methyl-N-hydroxyethylamino)ethyl, (N-methyl-N-hydroxyethylamino)propyl, (N-methyl-N-hydroxyethyl
  • the “(C 1 -C 6 alkyl)sulfonylamino-(C 1 -C 6 alkyl)” represents a group in which the above-described C 1 -C 6 alkyl is substituted with one amino and the amino is further substituted with one C 1 -C 6 alkylsulfonyl described below and may be, for example, methanesulfonylaminomethyl, ethanesulfonylaminomethyl, propanesulfonylaminomethyl, butanesulfonylaminomethyl, pentanesulfonylaminomethyl, hexanesulfonylaminomethyl, methanesulfonylaminoethyl, methanesulfonylaminopropyl, methanesulfonylaminobutyl, methanesulfonylaminopentyl or methanesulfonylaminohexyl, preferably (C 1 -
  • the “[N—(C 1 -C 6 alkyl)-N—(C 1 -C 6 alkyl)sulfonylamino]-(C 1 -C 6 alkyl)” represents a group in which the nitrogen atom of the above-described (C 1 -C 6 alkyl)sulfonylamino-(C 1 -C 6 alkyl) is substituted with one C 1 -C 6 alkyl described above and may be, for example, (N-methyl-N-methanesulfonylamino)methyl, (N-methyl-N-ethanesulfonylamino)methyl, (N-methyl-N-propanesulfonylamino)methyl, (N-methyl-N-butanesulfonylamino)methyl, (N-methyl-N-pentanesulfonylamino)methyl, (N-methyl-N-hexanesulfonylamino)methyl, (N-methyl-N-me
  • the “carboxy(C 1 -C 6 alkyl)” represents the above-described C 1 -C 6 alkyl which is substituted with 1 or 2 carboxy groups and may be, for example, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl, dicarboxypropyl, dicarboxybutyl, dicarboxypentyl or dicarboxyhexyl, preferably carboxy(C 1 -C 4 alkyl), more preferably carboxy(C 3 -C 4 alkyl), and most preferably 4-carboxy-1-butyl.
  • halogeno(C 1 -C 6 alkyl) represents the above-described C 1 -C 6 alkyl which is substituted with 1 to 7 halogeno groups described below that are independently selected, and may be, for example, fluoromethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, fluoroethyl, chloroethyl, bromoethyl, iodoethyl, difluoroethyl, trifluoroethyl, trichloroethyl, pentafluoroethyl, fluoropropyl, chloropropyl, fluorobutyl, trifluorobutyl, fluoropentyl or fluorohexyl.
  • the halogeno(C 1 -C 6 alkyl) in R 1 is preferably halogeno(C 1 -C 4 alkyl) in which the halogeno is 1 to 5 groups selected from the group consisting of fluoro and chloro, more preferably halogeno(C 2 -C 4 alkyl) in which the halogeno is 1 to 5 fluoro groups, and most preferably 4,4,4-trifluoro-1-butyl.
  • the halogeno(C 1 -C 6 alkyl) in the substituent group ⁇ is preferably halogeno(C 1 -C 4 alkyl) in which the halogeno is 1 to 5 groups selected from the group consisting of fluoro and chloro, and more preferably halogeno(C 1 -C 2 alkyl) in which the halogeno is 1 to 5 fluoro groups.
  • the “(C 3 -C 8 cycloalkyl)-(C 1 -C 6 alkyl)” represents the above-described C 1 -C 6 alkyl which is substituted with one C 3 -C 8 cycloalkyl described below and may be, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclopropylpropyl, cyclopropylbutyl, cyclopropylpentyl or cyclopropylhexyl, preferably (C 3 -C 6 cycloalkyl)-(C 1 -C 4 alkyl), and more preferably (C 3 -C 4 cycloalkyl)-(C 1 -C 2 alkyl).
  • C 2 -C 6 alkenyl represents straight or branched alkenyl which has 2 to 6 carbon atoms and has one or more carbon-carbon double bonds and may be, for example, vinyl, propenyl (for example, allyl), butenyl, pentenyl or hexenyl, preferably C 2 -C 5 alkenyl, more preferably C 3 -C 5 alkenyl, and most preferably 3-methyl-but-1-en-1-yl.
  • C 2 -C 6 alkynyl represents straight or branched alkynyl which has 2 to 6 carbon atoms and has one or more carbon-carbon triple bond and may be, for example, ethynyl, propynyl, butynyl, pentynyl or hexynyl, and preferably C 3 -C 5 alkynyl.
  • C 3 -C 8 cycloalkyl represents cyclic alkyl which has 3 to 8 carbon atoms and may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, preferably C 3 -C 6 cycloalkyl, more preferably C 3 -C 4 cycloalkyl, and most preferably cyclopropyl.
  • C 3 -C 8 cycloalkenyl represents cyclic alkenyl which has 3 to 8 carbon atoms and has one or more carbon-carbon double bond and may be, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl or cyclooctenyl, preferably C 4 -C 6 cycloalkenyl, and most preferably 1-cyclohexenyl.
  • the “C 1 -C 6 alkoxy” represents hydroxy substituted with one C 1 -C 6 alkyl described above and may be, for example, methoxy, ethoxy, propoxy, butoxy, pentyloxy or hexyloxy.
  • the C 1 -C 6 alkoxy in R 1 is preferably methoxy, ethoxy, 2-propoxy, 2-methyl-1-propoxy or 3-methyl-1-butoxy.
  • the C 1 -C 6 alkoxy in the substituent group ⁇ is preferably C 1 -C 4 alkoxy, and more preferably C 1 -C 2 alkoxy.
  • hydroxy(C 1 -C 6 alkoxy) represents the above-described C 1 -C 6 alkoxy which is substituted with 1 to 4 hydroxy groups and may be, for example, hydroxymethoxy, hydroxyethoxy, hydroxypropoxy, hydroxybutoxy, hydroxypentyloxy, hydroxyhexyloxy, dihydroxypropoxy, dihydroxybutoxy, dihydroxypentyloxy, dihydroxyhexyloxy, trihydroxybutoxy, trihydroxypentyloxy, trihydroxyhexyloxy, tetrahydroxypentyloxy or tetrahydroxyhexyloxy, preferably hydroxy(C 2 -C 6 alkoxy), and most preferably 2-hydroxyethoxy, 3-hydroxy-1-propoxy, (2R)-2-hydroxy-1-propoxy, (2S)-2-hydroxy-1-propoxy, (2R)-2,3-dihydroxy-1-propoxy, (2S)-2,3-dihydroxy-1-propoxy, 2-hydroxy-2-methyl-1-propoxy, 3-hydroxy-2-(hydroxy
  • the “(C 1 -C 6 alkoxy)-(C 1 -C 6 alkoxy)” represents the above-described C 1 -C 6 alkoxy which is substituted with one C 1 -C 6 alkoxy described above and may be, for example, methoxymethoxy, ethoxymethoxy, propoxymethoxy, butoxymethoxy, pentyloxymethoxy, hexyloxymethoxy, methoxyethoxy, methoxypropoxy, methoxybutoxy, methoxypentyloxy or methoxyhexyloxy, and preferably (C 1 -C 4 alkoxy)-(C 1 -C 4 alkoxy).
  • (C 1 -C 6 alkyl)sulfonyl-(C 1 -C 6 alkoxy) represents the above-described C 1 -C 6 alkoxy which is substituted with one C 1 -C 6 alkylsulfonyl described below and may be, for example, methanesulfonylmethoxy, ethanesulfonylmethoxy, propanesulfonylmethoxy, butanesulfonylmethoxy, pentanesulfonylmethoxy, hexanesulfonylmethoxy, methanesulfonylethoxy, methanesulfonylpropoxy, methanesulfonylbutoxy, methanesulfonylpentyloxy or methanesulfonylhexyloxy, preferably (C 1 -C 4 alkyl)sulfonyl-(C 1 -C 4 alkoxy), more preferably (
  • the “carboxy(C 1 -C 6 alkoxy)” represents the above-described C 1 -C 6 alkoxy which is substituted with 1 or 2 carboxy groups and may be, for example, carboxymethoxy, carboxyethoxy, carboxypropoxy, carboxybutoxy, carboxypentyloxy, carboxyhexyloxy, dicarboxypropoxy, dicarboxybutoxy, dicarboxypentyloxy or dicarboxyhexyloxy, preferably carboxy(C 2 -C 5 alkoxy), more preferably carboxy(C 3 -C 4 alkoxy), and most preferably 4-carboxy-1-butoxy.
  • halogeno(C 1 -C 6 alkoxy) represents the above-described C 1 -C 6 alkoxy which is substituted with 1 to 7 halogeno groups described below that are independently selected and may be, for example, fluoromethoxy, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, fluoroethoxy, chloroethoxy, bromoethoxy, iodoethoxy, difluoroethoxy, trifluoroethoxy, trichloroethoxy, pentafluoroethoxy, fluoropropoxy, chloropropoxy, fluorobutoxy, fluoropentyloxy or fluorohexyloxy.
  • the halogeno(C 1 -C 6 alkoxy) in R 1 is preferably halogeno(C 1 -C 4 alkoxy) in which the halogeno is 1 to 5 groups selected from the group consisting of fluoro and chloro, more preferably halogeno(C 1 -C 3 alkoxy) in which the halogeno is 1 to 5 fluoro groups, and most preferably difluoromethoxy or 3,3,3-trifluoro-1-propoxy.
  • the halogeno(C 1 -C 6 alkoxy) in the substituent group ⁇ is preferably halogeno(C 1 -C 4 alkoxy) in which the halogeno is 1 to 5 groups selected from the group consisting of fluoro and chloro, and more preferably halogeno(C 1 -C 2 alkoxy) in which the halogeno is 1 to 5 fluoro groups.
  • C 1 -C 6 alkylthio represents mercapto (—SH) which is substituted with one C 1 -C 6 alkyl described above and may be, for example, methylthio, ethylthio, propylthio, butylthio, pentylthio or hexylthio, preferably C 1 -C 4 alkylthio, more preferably C 1 -C 2 alkylthio, and most preferably methylthio.
  • C 1 -C 6 alkylsulfinyl represents sulfinyl (—SO—) which is substituted with one C 1 -C 6 alkyl described above and may be, for example, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, pentylsulfinyl or hexylsulfinyl, preferably C 1 -C 4 alkylsulfinyl, and more preferably C 1 -C 2 alkylsulfinyl.
  • C 1 -C 6 alkylsulfonyl represents sulfonyl (—SO 2 —) which is substituted with one C 1 -C 6 alkyl described above and may be, for example, methanesulfonyl, ethanesulfonyl, propanesulfonyl, butanesulfonyl, pentanesulfonyl or hexanesulfonyl, preferably C 1 -C 4 alkylsulfonyl, more preferably C 1 -C 2 alkylsulfonyl, and most preferably methanesulfonyl.
  • C 1 -C 6 alkylamino represents amino which is substituted with one C 1 -C 6 alkyl described above and may be, for example, methylamino, ethylamino, propylamino, butylamino, pentylamino or hexylamino, preferably C 1 -C 4 alkylamino, and more preferably C 1 -C 2 alkylamino.
  • di(C 1 -C 6 alkyl)amino represents amino which is substituted with two C 1 -C 6 alkyl groups described above that are independently selected and may be, for example, dimethylamino, ethylmethylamino, methylpropylamino, butylmethylamino, methylpentylamino, hexylmethylamino, diethylamino, ethylpropylamino, butylethylamino, dipropylamino, butylpropylamino, dibutylamino, dipentylamino or dihexylamino, preferably di(C 1 -C 4 alkyl)amino, and more preferably di(C 1 -C 2 alkyl)amino.
  • hydroxy(C 1 -C 6 alkyl)amino represents amino which is substituted with one hydroxy(C 1 -C 6 alkyl) described above and may be, for example, hydroxymethylamino, hydroxyethylamino, hydroxypropylamino, hydroxybutylamino, hydroxypentylamino, hydroxyhexylamino, dihydroxypropylamino, dihydroxybutylamino, dihydroxypentylamino, dihydroxyhexylamino, trihydroxybutylamino, trihydroxypentylamino, trihydroxyhexylamino, tetrahydroxypentylamino or tetrahydroxyhexylamino, and preferably hydroxy(C 1 -C 4 alkyl)amino.
  • N—(C 1 -C 6 alkyl)-N-hydroxy(C 1 -C 6 alkyl)amino represents amino which is substituted with one hydroxy(C 1 -C 6 alkyl) described above and one C 1 -C 6 alkyl described above and may be, for example, N-methyl-N-hydroxymethylamino, N-methyl-N-hydroxyethylamino, N-methyl-N-hydroxypropylamino, N-methyl-N-hydroxybutylamino, N-methyl-N-hydroxypentylamino, N-methyl-N-hydroxyhexylamino, N-ethyl-N-hydroxyethylamino, N-propyl-N-hydroxyethylamino, N-butyl-N-hydroxyethylamino, N-pentyl-N-hydroxyethylamino or N-hexyl-N-hydroxyethylamino, preferably N—(C 1 -C 4 alkyl)
  • the “(C 1 -C 6 alkyl)carbonylamino” represents a group in which the carbon atom of carbonylamino (—CONH—) is substituted with one C 1 -C 6 alkyl described above and may be, for example, methylcarbonylamino (acetylamino), ethylcarbonylamino, propylcarbonylamino, butylcarbonylamino, pentylcarbonylamino or hexylcarbonylamino, preferably (C 1 -C 4 alkyl)carbonylamino, and more preferably (C 1 -C 2 alkyl)carbonylamino.
  • the “(C 1 -C 6 alkoxy)carbonyl” represents carbonyl (—CO—) which is substituted with one C 1 -C 6 alkoxy described above and may be, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl or hexyloxycarbonyl, preferably (C 1 -C 4 alkoxy)carbonyl, and more preferably (C 1 -C 2 alkoxy)carbonyl.
  • the (C 1 -C 6 alkoxy)carbonyl in the substituent group ⁇ is preferably (C 1 -C 4 alkoxy)carbonyl, more preferably (C 1 -C 2 alkoxy)carbonyl, and most preferably ethoxycarbonyl.
  • the “(C 1 -C 6 alkylamino)carbonyl” represents carbonyl (—CO—) which is substituted with one C 1 -C 6 alkylamino described above and may be, for example, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, butylaminocarbonyl, pentylaminocarbonyl or hexylaminocarbonyl, preferably (C 1 -C 4 alkylamino)carbonyl, more preferably (C 1 -C 2 alkylamino)carbonyl, and most preferably methylaminocarbonyl.
  • di(C 1 -C 6 alkyl)aminocarbonyl represents carbonyl (—CO—) which is substituted with one di(C 1 -C 6 alkyl)amino described above and may be, for example, dimethylaminocarbonyl, (N-ethyl-N-methylamino)carbonyl, (N-methyl-N-propylamino)carbonyl, (N-butyl-N-methylamino)carbonyl, (N-methyl-N-pentylamino)carbonyl, (N-hexyl-N-methylamino)carbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, dibutylaminocarbonyl, dipentylaminocarbonyl or dihexylaminocarbonyl, preferably di(C 1 -C 4 alkyl)aminocarbonyl, more preferably di(C 1 -C 2 alkyl)aminocarbonyl,
  • halogeno may be fluoro, chloro, bromo or iodo, and preferably fluoro, chloro or bromo.
  • the “5- or 6-membered aromatic heterocyclyl” represents a 5- or 6-membered aromatic heterocyclic group which contains 1 to 4 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and may be, for example, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl, preferably 5- or 6-membered nitrogen-containing aromatic heterocyclyl, more preferably 5-membered nitrogen-containing aromatic heterocyclyl, and most preferably oxadiazolyl.
  • the “5- or 6-membered saturated heterocyclyl” represents a 5- or 6-membered saturated heterocyclic group which contains 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and may be, for example, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, thioxanyl, dithianyl, trioxanyl or trithianyl, preferably 5- or 6-membered nitrogen-containing saturated heterocyclyl, and more preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl.
  • the “5- or 6-membered saturated heterocyclyl-(C 1 -C 6 alkyl)” represents the above-described C 1 -C 6 alkyl which is substituted with one 5- or 6-membered saturated heterocyclyl described above and may be, for example, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl or thiomorpholinylmethyl, preferably 5- or 6-membered nitrogen-containing saturated heterocyclyl-(C 1 -C 4 alkyl), and more preferably 5- or 6-membered nitrogen-containing saturated heterocyclyl-(C 1 -C 2 alkyl).
  • the “5- or 6-membered saturated heterocyclyloxy” represents hydroxy which is substituted with one 5- or 6-membered saturated heterocyclyl described above and may be, for example, pyrrolidinyloxy, piperidinyloxy, piperazinyloxy, morpholinyloxy or thiomorpholinyloxy, preferably 5- or 6-membered nitrogen-containing saturated heterocyclyloxy, and more preferably pyrrolidinyloxy or piperidinyloxy.
  • the heteroatom of the heterocyclyl portion is not directly bonded to the oxygen atom of the oxy portion.
  • the “5- or 6-membered saturated heterocyclylcarbonyl” represents carbonyl (—CO—) which is substituted with one 5- or 6-membered saturated heterocyclyl described above and may be, for example, pyrrolidinylcarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl or thiomorpholinylcarbonyl, preferably 5- or 6-membered nitrogen-containing saturated heterocyclylcarbonyl, and most preferably morpholinylcarbonyl.
  • the nitrogen atom of the nitrogen-containing saturated heterocyclyl portion binds to the carbonyl portion.
  • the compound represented by general formula (I) or a pharmacologically acceptable salt thereof of the present invention has one or more of an asymmetric center, carbon-carbon double bond, axial chirality and the like, optical isomers (including enantiomers and diastereomers), geometric isomers, tautomers and rotational isomers may exist, and these isomers and mixtures thereof are described by a single formula such as general formula (I).
  • the present invention encompasses each of these isomers and mixtures thereof at any ratio (including racemates).
  • the compound represented by general formula (I) in the present invention encompasses a compound represented by general formula (I-1), (I-2), (I-3) or (I-4) or mixtures thereof (including racemates and diastereomer mixtures) and is preferably a compound represented by general formula (I-1) or (I-2) or mixtures thereof (including racemates), and more preferably a compound represented by general formula (I-1).
  • the compound represented by general formula (I-1) may contain a certain amount of a compound represented by general formula (I-2), (I-3) or (I-4).
  • the “compound represented by general formula (I-1)” in the present invention encompasses “a compound represented by general formula (I-1) which contains a certain amount of a compound represented by general formula (I-2), (I-3) or (I-4)” and preferably encompasses “a compound represented by general formula (I-1) which contains a certain amount of a compound represented by general formula (I-2)”, “a compound represented by general formula (I-1) which contains a certain amount of a compound represented by general formula (I-3)” and “a compound represented by general formula (I-1) which contains a certain amount of a compound represented by general formula (I-4)”.
  • the percentage content of the compound represented by general formula (I-2), (I-3) or (I-4) in the compound represented by the general formula (I-1) may be for example, 5% or less, preferably 3% or less, more preferably 1% or less, further preferably 0.5% or less, further more preferably 0.3% or less, particularly preferably 0.1% or less, and most preferably 0.05% or less.
  • the above-described percentage content of the compound represented by the general formulae (I-2), (I-3) or (I-4) may be calculated, for example, using the peak area ratio in high performance liquid chromatography (HPLC) or the weight ratio, and preferably the peak area ratio in HPLC.
  • the compound represented by general formula (I) of the present invention may form an acid addition salt and the acid addition salt thereof may be, for example, a hydrochloric acid salt, a hydrobromic acid salt, a sulfuric acid salt, a nitric acid salt, a phosphoric acid salt, an acetic acid salt, an oxalic acid salt, a malonic acid salt, a fumaric acid salt, a maleic acid salt, a phthalic acid salt, a trifluoroacetic acid salt, a methanesulfonic acid salt, a benzenesulfonic acid salt, a p-toluenesulfonic acid salt, a 2,4-dimethyl benzenesulfonic acid salt, a 2,4,6-trimethyl benzenesulfonic acid salt, a 4-ethyl benzenesulfonic acid salt or a naphthalenesulfonic acid salt.
  • a hydrochloric acid salt a
  • the acid addition salt thereof is encompassed in the pharmacologically acceptable salt of the present invention.
  • the compound represented by general formula (I) of the present invention may form an acid addition salt with an acid at any ratio and each of them (for example, a monohydrochloride, a dihydrochloride or the like) or a mixture thereof is encompassed in the present invention.
  • the compound represented by general formula (I) of the present invention may form a base addition salt and the base addition salt thereof may be, for example, a metal salt, an inorganic amine salt, an organic amine salt or an amino acid salt.
  • the metal salt may be, for example, an alkali metal salt such as a sodium salt, a potassium salt and a lithium salt; an alkaline earth metal salt such as a calcium salt and a magnesium salt; an aluminum salt; an iron salt; a zinc salt; a copper salt; a nickel salt; or a cobalt salt.
  • the inorganic amine salt may be, for example, an ammonium salt.
  • the organic amine salt may be, for example, a morpholine salt, a glucosamine salt, an ethylenediamine salt, a guanidine salt, a diethylamine salt, a triethylamine salt, a dicyclohexylamine salt, a diethanolamine salt, a piperazine salt or a tetramethylammonium salt.
  • the amino acid salt may be, for example, a glycine salt, a lysine salt, an arginine salt, an ornithine salt, a glutamic acid salt or an aspartic acid salt.
  • the base addition salt thereof is encompassed in the pharmacologically acceptable salt of the present invention.
  • the acid addition salt or base addition salt of the compound represented by general formula (I) of the present invention may be prepared in the method described below, for example:
  • the compound represented by general formula (I) of the present invention has a group which may form an ester group such as a hydroxy group or a carboxy group
  • the compound may be converted to a pharmacologically acceptable ester and this pharmacologically acceptable ester is encompassed in the present invention.
  • the pharmacologically acceptable ester of the compound represented by general formula (I) may be a prodrug of the compound represented by general formula (I) and be decomposed in a metabolic process (for example, hydrolysis) when administered to a living body of a warm-blooded animal to produce the compound represented by general formula (I).
  • the group which may form an ester group with a hydroxy group may be, for example, aliphatic acyl [for example, (C 1 -C 20 alkyl)carbonyl], aromatic acyl or alkoxycarbonyl [for example, (C 1 -C 6 alkoxy)carbonyl].
  • the group which may form an ester group with a carboxy group may be, for example, aliphatic alkyl [for example, a C 1 -C 6 alkyl], alkylcarbonyloxyalkyl [for example, (C 1 -C 6 alkyl)carbonyloxy-(C 1 -C 6 alkyl)], cycloalkylcarbonyloxyalkyl [for example, (C 3 -C 8 cycloalkyl)carbonyloxy-(C 1 -C 6 alkyl)], alkoxycarbonyloxyalkyl [for example, (C 1 -C 6 alkoxy)carbonyloxy-(C 1 -C 6 alkyl)] or cycloalkyloxycarbonyloxyalkyl [for example, (C 3 -C 8 cycloalkyl)oxycarbonyloxy-(C 1 -C 6 alkyl)].
  • alkylcarbonyloxyalkyl for example, (C 1 -C 6 alkyl)carbon
  • the compound represented by general formula (I) or a pharmacologically acceptable salt thereof of the present invention may form a hydrate or a solvate. Each of these or a mixture thereof is encompassed in the present invention.
  • the compound represented by general formula (I) or a pharmacologically acceptable salt thereof of the present invention may form an isotopic compound in which one or more atom constituting the compound is substituted with an isotopic atom at non-natural ratio.
  • the isotopic atom may be radioactive or non-radioactive, for example, deuterium ( 2 H; D), tritium ( 3 H; T), carbon-14 ( 14 C), iodine-125 ( 125 I) and the like.
  • the radioactive or non-radioactive isotopic compound may be used as a medicament for treatment or prophylaxis of a disease, a reagent for research (for example, a reagent for assay), a diagnostic medicament (for example, an image diagnostic medicament) and the like.
  • the present invention encompasses a radioactive or non-radioactive isotopic compound.
  • the “dyslipidemia” in the present invention encompasses hyperlipidemia.
  • the “arteriosclerosis” encompasses (i) arteriosclerosis due to various factors such as smoking and genetics (including multiple factors); and (ii) arteriosclerosis due to a disease which may cause arteriosclerosis such as dyslipidemia, low HDL cholesterolemia, high LDL cholesterolemia, a lipid-related disease, an inflammatory disease, diabetes, obesity or hypertension, and encompasses, for example, atherosclerosis, arteriolosclerosis, arteriosclerosis obliterans and atheromatous atherosclerosis.
  • the “arteriosclerotic heart disease” represents a heart vascular disease which develops due to arteriosclerosis as one of the causes.
  • a coronary heart disease represents a heart vascular disease which develops due to arteriosclerosis or other diseases as one of the causes and encompasses, for example, heart failure, myocardial infarction, angina pectoris, cardiac ischemia, cardiovascular disorder or angioplasty-related restenosis.
  • the “cerebrovascular disease” encompasses, for example, stroke or cerebral infarction.
  • the “peripheral vascular disease” encompasses, for example, diabetic vascular complications.
  • the compound represented by general formula (I) or a pharmacologically acceptable salt thereof of the present invention may form a pharmaceutical composition in combination with other medicaments depending on the purpose.
  • the pharmaceutical composition may be (i) a combination of a formulation which contains the compound represented by general formula (I) or a pharmacologically acceptable salt thereof of the present invention as an active ingredient and a formulation which contains other medicaments as an active ingredient; or (ii) a single formulation (combination drug) which contains both of the compound represented by general formula (I) or a pharmacologically acceptable salt thereof of the present invention and the other medicaments as an active ingredient, and preferably the combination drug.
  • the pharmaceutical composition may be administered simultaneously or separately at an interval.
  • the dosage form is not particularly limited as long as it is a dosage form in which the pharmaceutical composition may be administered separately at a different time.
  • the time from administration of one active ingredient to administration of another active ingredient is not particularly limited and the other active ingredient is preferably administered within a time when the action of the previously administered active ingredient persists.
  • the other medicament which may be used in combination with the compound represented by general formula (I) or a pharmacologically acceptable salt thereof of the present invention is not particularly limited as long as it has effects depending on the purpose thereof.
  • the compound represented by general formula (I) of the present invention [hereinafter, also referred to as the compound (I); the same for other formulae] can be prepared according to Method A (Methods A-1, A-2, A-3 and A-4), Method B (Methods B-1 and B-2), Method C, Method D, Method E or Method F described below.
  • R 1 represents the same meanings as those in general formula (I);
  • R a represents a C 1 -C 6 alkyl group, a hydroxy(C 1 -C 6 alkyl) group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) group, a (C 1 -C 6 alkyl)sulfonyl-(C 1 -C 6 alkyl) group, a carboxy(C 1 -C 6 alkyl) group or a halogeno(C 1 -C 6 alkyl) group;
  • the group represented by the formula R a O— represents a C 1 -C 6 alkoxy group, a hydroxy(C 1 -C 6 alkoxy) group, a (C 1 -C 6 alkoxy)-(C 1 -C 6 alkoxy) group, a (C 1 -C 6 alkyl)sulfonyl-(
  • the acid used in the reaction of each step of Methods A to F described below is not particularly limited as long as it does not inhibit the reaction and is selected from the group of acids described below.
  • the group of acids consists of organic acids such as acetic acid, propionic acid, trifluoroacetic acid or pentafluoropropionic acid; organic sulfonic acids such as p-toluenesulfonic acid, camphorsulfonic acid or trifluoromethanesulfonic acid; and inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid or nitric acid.
  • the base used in the reaction of each step of Methods A to F described below is not particularly limited as long as it does not inhibit the reaction and is selected from the group of bases described below.
  • the group of bases consists of alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate or cesium carbonate; alkali metal hydrogencarbonate such as lithium hydrogencarbonate, sodium hydrogencarbonate or potassium hydrogencarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide or barium hydroxide; alkali metal hydrides such as lithium hydride, sodium hydride or potassium hydride; alkali metal amides such as lithium amide, sodium amide or potassium amide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide; lithium alkyl amides such as lithium diisopropylamide
  • the solvent used in the reaction of each step of Methods A to F described below is not particularly limited as long as it does not inhibit the reaction and partially dissolves starting raw materials and for example, is selected from the group of solvents described below.
  • the group of solvents consists of aliphatic hydrocarbons such as hexane (for example, n-hexane), pentane (for example, n-pentane), heptane (for example, n-heptane), petroleum ether or cyclohexane; aromatic hydrocarbons such as benzene, toluene, xylene or ethyl benzene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,
  • reaction temperature varies depending on the solvent, starting raw materials, reagents or the like
  • reaction time varies depending on the solvent, starting raw materials, reagents, reaction temperature or the like.
  • the desired compound of each step may be isolated from the reaction mixture after the reaction completion according to a method which is well known in the field of organic chemistry.
  • the desired compound is obtained, for example, by (i) filtering off insoluble materials such as a catalyst as necessary, (ii) adding water and a solvent which is immiscible with water (for example, dichloromethane, diethyl ether, ethyl acetate or the like) to the reaction mixture and extracting the desired compound, (iii) washing the organic layer with water and drying it with a drying agent such as anhydrous magnesium sulfate, and (iv) distilling off the solvent.
  • a solvent which is immiscible with water for example, dichloromethane, diethyl ether, ethyl acetate or the like
  • the obtained desired compound may be further purified by a method which is well known in the field of organic chemistry (for example, recrystallization, reprecipitation, silica gel column chromatography or the like) as necessary.
  • the desired compound of each process may be also used in the next reaction as it is without purification.
  • a protective group for such groups and removal of the introduced protective group may be performed suitably as necessary.
  • a protective group is not particularly limited as long as it is a protective group usually used and may be, for example, a protective group described in T. W. Greene, P. G. Wuts, Greene's Protective Groups in Organic Synthesis, Fourth Edition, 2007, John Wiley & Sons, Inc. and the like.
  • the introduction reaction of such a protective group and the removal reaction of the protective group may be performed according to a method which is well known in the field of organic chemistry (for example, a method as described in the above-described literature).
  • isolation of a single diastereomer (a racemate) from a mixture of two kinds of diastereomers (a mixture of four kinds of enantiomers) may be performed by column chromatography, a crystallization method or the like and isolation of a single enantiomer from a single diastereomer (a racemate) may be performed by optically active column chromatography, a fractional crystallization method using an optically active compound (for example, an optically active carboxylic acid compound or an optically active amine compound) or the like.
  • Isolation of a single enantiomer from a mixture of two kinds of diastereomers (a mixture of four kinds of enantiomers) may be performed by optically active column chromatography in any step.
  • Step A-7 isolation of a single diastereomer (a racemate) from a mixture of two kinds of diastereomers is performed in Step A-7 and isolation of a single enantiomer from a single diastereomer (a racemate) is performed in Step A-10.
  • the compounds (10), (11) and (12) are the single diastereomers (racemates) described in Reference Examples 7, 8 and 9, respectively and the compound (13) is the single enantiomer described in Reference Example 10.
  • Isolation of a single diastereomer (a racemate) and isolation of a single enantiomer are not limited to the above-described examples and may be performed in any process (the same or different process) of Methods A to F, respectively.
  • Step A-7 Steps A-8 to A-9, Steps A-11 to A-14, Steps B-1 to B-4, Steps C-1 to C-2, Steps D-1 to D-2, Steps E-1 to E-3 or Steps F-1 may be performed respectively using a mixture of two kinds of diastereomers as a raw material.
  • the steps following those may be performed respectively using the single diastereomer (a racemate) as a raw material.
  • the process following those may be performed respectively using the single enantiomer as a raw material and the compound (I) [preferably the compound (I-1)] as a single enantiomer is obtained.
  • the compound (I) as a single diastereomer (a racemate) is obtained and the compound (I) [preferably, the compound (I-1)] as a single enantiomer is obtained by further performing isolation of a single enantiomer.
  • the compound (I) as a mixture of two kinds of diastereomers is obtained and the compound (I) [preferably, the compound (I-1)] as a single enantiomer is obtained by performing isolation of a single diastereomer (a racemate) and isolation of a single enantiomer.
  • Method A is a method of preparing the compounds (Ia) and (Ib) which are encompassed in the compound (I).
  • Step A-1 is a step of preparing the compound (2) by reducing the compound (1).
  • the compound (1) is known.
  • the reduction reagent to be used is not limited as long as it may be used in the reduction reaction of an alkoxycarbonyl group to a formyl group and is preferably diisobutyl aluminum hydride.
  • the solvent to be used is preferably an aromatic hydrocarbon, and more preferably toluene.
  • the reaction temperature is preferably ⁇ 100° C. to 0° C.
  • the reaction time is preferably 30 minutes to 12 hours.
  • Step A-2 is a step of preparing the compound (4) by reacting the compound (3) with acetonitrile in the presence of a base.
  • the compound (3) is known.
  • a protective group which is well known in the field of organic chemistry may be used as the protective group of the amino group in the compound (3) instead of the tert-butoxycarbonyl group (for example, T. W. Greene, P. G. Wuts, Greene's Protective Groups in Organic Synthesis, Fourth Edition, 2007, John Wiley & Sons, Inc.).
  • the base to be used is preferably a lithium alkyl amide, and more preferably lithium diisopropylamide.
  • the solvent to be used is preferably an aliphatic hydrocarbon, aromatic hydrocarbon, ether or a mixture thereof, and more preferably n-heptane, ethylbenzene, tetrahydrofuran or a mixture thereof.
  • the reaction temperature is preferably ⁇ 78° C. to 50° C.
  • the reaction time is preferably 30 minutes to 48 hours.
  • Step A-3 is a step of preparing the compound (6) by reacting the compounds (2) and (4) and then reacting the compound (5).
  • the compound (5) is known. An excess amount of the compound (5) may be used in Step A-3.
  • the solvent to be used is preferably an aromatic hydrocarbon, and more preferably toluene.
  • the reaction temperature is preferably 50° C. to 150° C.
  • the reaction time is preferably 30 minutes to 48 hours.
  • Step A-4 is a step of preparing the compound (7) by oxidizing the compound (6).
  • the oxidation reagent to be used is not limited as long as it may be used in the oxidation reaction of a dihydropyridyl group to a pyridyl group, and is preferably 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).
  • DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone
  • the solvent to be used is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • the reaction temperature is preferably 0° C. to 50° C.
  • the reaction time is preferably 30 minutes to 12 hours.
  • Step A-5 is a step of preparing the compound (8) by reducing the compound (7).
  • the reduction reagent to be used is not limited as long as it may be used in the reduction reaction of a cyano group to a formyl group and is preferably diisobutyl aluminum hydride.
  • the solvent to be used is preferably an aromatic hydrocarbon, and more preferably toluene.
  • the reaction temperature is preferably ⁇ 100° C. to 0° C.
  • the reaction time is preferably 30 minutes to 12 hours.
  • Step A-6 is a step of preparing the compound (9) by reacting the compound (8) with p-methoxybenzyl bromide in the presence of a base.
  • the base to be used is not limited as long as it may be used in the alkylation reaction of a hydroxy group and is preferably an alkali metal hydride, and more preferably sodium hydride.
  • the solvent to be used is preferably an amide, and more preferably N,N-dimethylformamide.
  • the reaction temperature is preferably ⁇ 50° C. to 50° C.
  • the reaction time is preferably 30 minutes to 12 hours.
  • Step A-6 a protective group which is well known in the field of organic chemistry may be used as the protective group of the hydroxy group instead of the p-methoxybenzyl group (for example, T. W. Greene, P. G. Wuts, Greene's Protective Groups in Organic Synthesis, Fourth Edition, 2007, John Wiley & Sons, Inc.).
  • Step A-7 is a step of preparing the compound (10) by reacting the compound (9) with 4-trifluoromethylphenyl magnesium bromide.
  • 4-Trifluoromethylphenyl magnesium bromide can be prepared by a method which is well known in the field of organic chemistry from 4-trifluoromethylphenyl bromide and magnesium.
  • the solvent to be used is preferably an ether, and more preferably tetrahydrofuran.
  • the reaction temperature is preferably ⁇ 20° C. to 50° C.
  • the reaction time is preferably 30 minutes to 12 hours.
  • the compound (10) has two asymmetric carbon atoms (the carbon atoms to which a hydroxy group or a p-methoxybenzyloxy group is bonded) and may be obtained as a mixture of stereoisomers (a mixture of four kinds of optical isomers, namely, a mixture of diastereomers).
  • the diastereomer mixture obtained in Step A-7 may be isolated into single diastereomer compounds depending on the properties of the mixture. This isolation may be performed by a method which is well known in the field of organic chemistry (for example, resolution by column chromatography or fractional crystallization of a diastereomer mixture).
  • Each of the isolated diastereomer compounds may be isolated into single enantiomer compounds depending on the properties of the compound. This isolation may be performed by a method which is well known in the field of organic chemistry (for example, optical resolution by column chromatography or fractional crystallization with formation of diastereomer salt).
  • Step A-7 this is the same in the case of the compound which is obtained using a protective group other than the p-methoxybenzyloxy group and the tert-butoxycarbonyl group as the two protective groups in the compound (9).
  • This is the same in the case of the compound (11) which is obtained in Step A-8.
  • Step A-8 is a step of preparing the compound (11) by reacting the compound (10) with a fluorination reagent.
  • the fluorination reagent to be used is not limited as long as it may be used in the fluorination reaction of a hydroxy group and is preferably bis(methoxyethyl)aminosulfur trifluoride [Deoxo-Fluor (trade name)].
  • the solvent to be used is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • the reaction temperature is preferably ⁇ 100° C. to 0° C.
  • the reaction time is preferably 30 minutes to 24 hours.
  • Step A-9 is a step of preparing the compound (12) by reacting the compound (11) with zinc bromide.
  • the solvent to be used is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • the reaction temperature is preferably 0° C. to 50° C.
  • the reaction time is preferably 1 hour to 5 days.
  • the diastereomer mixture obtained in Step A-9 may be isolated into single diastereomer compounds and the compound (12) may be obtained as a single diastereomer compound.
  • the removal reaction of the tert-butoxycarbonyl group in Step A-9 may be also performed by a method which is well known in the field of organic chemistry (for example, T. W. Greene, P. G. Wuts, Greene's Protective Groups in Organic Synthesis, Fourth Edition, 2007, John Wiley & Sons, Inc.).
  • Step A-10 is a step of obtaining the compound (13) as a single enantiomer by subjecting the compound (12) to optical resolution by optically active column chromatography.
  • optically active column and the resolution conditions to be used are not limited as long as they can achieve optical resolution of the compound (12) and are preferably those described in Reference Example 10.
  • Step A-11 is a step of preparing the compound (14) by reacting the compound (13) with 5-bromo-2-chloropyrimidine in the presence of a base.
  • the base to be used is preferably an organic amine, and more preferably diisopropylethylamine or 1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU).
  • DBU 1,8-diazabicyclo[5,4,0]undeca-7-ene
  • the solvent to be used is preferably an ether or amide, and more preferably 1,4-dioxane.
  • the reaction temperature is preferably 20° C. to 150° C.
  • the reaction time is preferably 30 minutes to 12 hours.
  • Step A-12 is a step of preparing the compound (15) by reacting the compound (14) with morpholine in the presence of a palladium catalyst, a phosphorus reagent and a base.
  • the palladium catalyst to be used is not limited as long as it may be used in the amination reaction on the aromatic ring and may be, for example, a palladium catalyst described in J. Tsuji, Palladium Reagents and Catalysis: New Perspectives for the 21st Century, 2004, John Wiley & Sons, Inc., and the like.
  • the palladium catalyst to be used is preferably tetrakis(triphenyl phosphine) palladium (0), tris(dibenzylidene acetone)dipalladium (0), palladium chloride (II), palladium acetate (II) or palladium dichlorobis(triphenyl phosphine) (II), and more preferably palladium acetate (11).
  • the phosphorus reagent to be used is not limited as long as it may be used in the amination reaction on the aromatic ring and is preferably 2-(di-tert-butylphosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 5-(di-tert-butylphosphino)-1′,3′,5′-triphenyl-1′H-[1,4′]bipyrazole, cyclohexyl phosphine, 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene or 2-(diphenylphosphino)-2′-(N,N-dimethylamino)biphenyl, and more preferably 2-dicyclohexylphosphino-2′,4′
  • the base to be used is preferably an alkali metal alkoxide, and more preferably sodium tert-butoxide.
  • the solvent to be used is preferably an aromatic hydrocarbon, alcohol or a mixture thereof, and more preferably toluene, 2-methyl-2-propanol or a mixture thereof.
  • the reaction temperature is preferably 20° C. to 150° C.
  • the reaction time is preferably 30 minutes to 12 hours.
  • the amination reaction may be performed using an optionally substituted 5- or 6-membered nitrogen-containing saturated cyclic amine other than morpholine instead of morpholine.
  • the palladium catalyst used in this amination reaction is preferably tris(dibenzylidene acetone)dipalladium (0) and stirring under microwave irradiation is preferable.
  • a compound in which R 1 in the compound (I) is an optionally substituted 5- or 6-membered nitrogen-containing saturated heterocyclyl group and the nitrogen atom binds to the 5-position of the pyrimidine may be prepared by removing the p-methoxybenzyl group in the compound obtained in the above-described reaction according to a method similar to that of Step B-4.
  • the carbon-carbon coupling reaction may be performed using a compound represented by a formula R g B(OH) 2 wherein R g represents a C 3 -C 8 cycloalkyl group, a C 3 -C 8 cycloalkenyl group, a phenyl group, a substituted phenyl group, a 5- or 6-membered aromatic heterocyclyl group or a substituted 5- or 6-membered aromatic heterocyclyl group, which are defined in R 1 , or boronic acid ester thereof instead of morpholine.
  • the palladium catalyst used in this carbon-carbon coupling reaction is preferably palladium acetate (II).
  • a compound in which R 1 is R g in the compound (I) can be prepared by removing the p-methoxybenzyl group in the compound obtained in the above-described reaction according to a method similar to that of Step B-4.
  • Step A-13 is a step of preparing the compound (Ia) by treating the compound (15) with an acid.
  • the acid to be used is preferably an inorganic acid, and more preferably hydrochloric acid.
  • the solvent to be used is preferably an ether, alcohol or a mixture thereof, and more preferably 1,4-dioxane, methanol or a mixture thereof.
  • the reaction temperature is preferably 20° C. to 150° C.
  • the reaction time is preferably 30 minutes to 6 hours.
  • Step A-14 is a step of preparing the compound (Ib) by reacting the compound (Ia) with the compound (16) in the presence of a base.
  • the base to be used is preferably an alkali metal carbonate, and more preferably cesium carbonate.
  • the solvent to be used is preferably an ether or amide, and more preferably tetrahydrofuran, N,N-dimethylformamide or 1-methyl-2-pyrrolidone.
  • the reaction temperature is preferably 0° C. to 100° C.
  • the reaction time is preferably 30 minutes to 50 hours.
  • Method B is a method of preparing the compound (Ic) which is encompassed in the compound (I).
  • Step B-1 is a step of preparing the compound (17) by reacting the compound (13) with 2-chloro-5-formyl pyrimidine in the presence of a base.
  • the base to be used is preferably an organic amine, and more preferably 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).
  • DBU 1,8-diazabicyclo[5,4,0]undec-7-ene
  • the solvent to be used is preferably an amide, and more preferably 1-methyl-2-pyrrolidone.
  • the reaction temperature is preferably 0° C. to 100° C.
  • the reaction time is preferably 30 minutes to 12 hours.
  • Step B-2 is a step of preparing the compound (18) by reducing the compound (17).
  • the reduction reagent to be used is not limited as long as it may be used in the reduction reaction of a formyl group to a hydroxy group and is preferably an alkali metal borohydride such as sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and lithium borohydride, and more preferably sodium borohydride.
  • an alkali metal borohydride such as sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and lithium borohydride, and more preferably sodium borohydride.
  • the solvent to be used is preferably an ether, alcohol or a mixture thereof, and more preferably tetrahydrofuran, ethanol or a mixture thereof.
  • the reaction temperature is preferably ⁇ 20° C. to 50° C.
  • the reaction time is preferably 10 minutes to 6 hours.
  • Step B-3 is a step of preparing the compound (20) by reacting the compound (18) with methanesulfonyl chloride in the presence of a base followed by the compound (19).
  • the compound (19) is known.
  • the base to be used is preferably an organic amine, and more preferably diisopropylethylamine.
  • the solvent to be used is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • the reaction temperature is preferably 0° C. to 100° C.
  • the reaction time is preferably 10 minutes to 6 hours.
  • Step B-4 is a step of preparing the compound (Ic) by removing the p-methoxybenzyl group in the compound (20) in the presence of anisole and an acid.
  • the acid to be used is preferably an organic acid, and more preferably trifluoroacetic acid.
  • the solvent to be used is preferably a halogenated hydrocarbon, and more preferably dichloromethane.
  • the reaction temperature is preferably 0° C. to 100° C.
  • the reaction time is preferably 30 minutes to 48 hours.
  • the removal reaction of the p-methoxybenzyl group in Step B-4 may be also performed by a method which is well known in the field of organic chemistry (for example, T. W. Greene, P. G. Wuts, Greene's Protective Groups in Organic Synthesis, Fourth Edition, 2007, John Wiley & Sons, Inc.).
  • Method C is a method of preparing the compound (1).
  • Step C-1 is a step of preparing the compound (22) by reacting the compound (13) with the compound (21) in the presence of a base.
  • the compound (21) is known, may be easily prepared from a known compound or may be prepared according to the Reference Examples. Step C-1 may be also performed using a palladium catalyst, a phosphorus reagent and a base, similar to those of Step A-12.
  • the base to be used is preferably an organic amine, and more preferably diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) or a mixture thereof.
  • DBU 1,8-diazabicyclo[5,4,0]undec-7-ene
  • the solvent to be used is preferably an ether, alcohol or amide, and more preferably 1,4-dioxane, 2-propanol, 2-methyl-2-propanol, N,N-dimethylformamide or 1-methyl-2-pyrrolidone.
  • the reaction temperature is preferably 20 to 160° C.
  • the reaction time is preferably 30 minutes to 12 hours.
  • Step C-1 may be performed under microwave irradiation.
  • Step C-2 is a step of preparing the compound (1) by removing the p-methoxybenzyl group in the compound (22) in the presence of anisole and an acid.
  • Step C-2 may be performed according to a method similar to that of Step B-4.
  • Method D is a method of preparing the compound (Id) which is encompassed in the compound (I).
  • Step D-1 is a step of preparing the compound (24) by reacting the compound (17) with the compound (23).
  • the compound (23) is known or may be easily prepared from a known compound.
  • the solvent to be used is preferably an ether, and more preferably tetrahydrofuran.
  • the reaction temperature is preferably 0° C. to 60° C.
  • the reaction time is preferably 10 minutes to 6 hours.
  • Step D-2 consists of
  • Step D-2A Step of removing the p-methoxybenzyl group in the compound (24) in the presence of an acid
  • Step D-2B Step of preparing the compound (Id) by subjecting the compound obtained in Step D-2A to a dehydration reaction or reduction reaction.
  • the removal reaction of the p-methoxybenzyl group and the dehydration reaction may proceed simultaneously.
  • the acid used in the reaction is preferably an inorganic acid or organic acid, and more preferably hydrochloric acid or trifluoroacetic acid.
  • the solvent to be used is preferably a halogenated hydrocarbon or ether, and more preferably dichloromethane or 1,4-dioxane.
  • the reaction temperature is preferably 0° C. to 110° C.
  • the reaction time is preferably 30 minutes to 48 hours.
  • the reduction reagent used in the reduction reaction is not limited as long as it may be used in the reduction reaction of a hydroxyl group and is preferably triethylsilane.
  • the removal reaction of the p-methoxybenzyl group in Step D-2 may also be performed by a method which is well known in the field of organic chemistry (for example, T. W. Greene, P. G. Wuts, Greene's Protective Groups in Organic Synthesis, Fourth Edition, 2007, John Wiley & Sons, Inc.).
  • Method E is a method of preparing the compound (Ie) which is encompassed in the compound (I).
  • Step E-1 is a step of preparing the compound (25) by oxidizing the compound (17).
  • the oxidation reagent to be used is not limited as long as it may be used in the oxidation reaction of a formyl group to a carboxyl group and is preferably potassium permanganate, sodium chlorite, sodium hypochlorite, hydrogen peroxide, chromic acid, meta-chloroperbenzoic acid, silver nitrate or pyridinium dichromate, and more preferably sodium chlorite.
  • potassium permanganate sodium chlorite, sodium hypochlorite, hydrogen peroxide, chromic acid, meta-chloroperbenzoic acid, silver nitrate or pyridinium dichromate, and more preferably sodium chlorite.
  • sodium chlorite is used as the oxidation reagent
  • 2-methyl-2-butene and sodium dihydrogen phosphate are preferably used in combination.
  • the solvent to be used is preferably an ether, alcohol, water or a mixture thereof, and more preferably tetrahydrofuran, tert-butanol, water or a mixture thereof.
  • the reaction temperature is preferably 0° C. to 70° C.
  • the reaction time is preferably 30 minutes to 6 hours.
  • Step E-2 is a step of preparing the compound (26) by reacting the compound (25) with an alcohol compound or an amine compound in the presence of a condensing reagent.
  • the condensing reagent to be used is not limited as long as it may be used in the condensing reaction of a carboxy group and a hydroxy group or an amino group and is preferably 1,1′-carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide or a combination thereof with 1-hydroxybenzotriazole.
  • a base may be used in combination with the above-described condensing reagent.
  • the base to be used is preferably an organic amine, and more preferably triethylamine.
  • the solvent to be used is preferably an ether, nitrile, amide or a mixture thereof, and more preferably tetrahydrofuran, acetonitrile, N,N-dimethyl acetamide or a mixture thereof.
  • the reaction temperature is preferably 0° C. to 120° C.
  • the reaction time is preferably 30 minutes to 6 hours.
  • Step E-3 is a step of preparing the compound (Ie) by removing the p-methoxybenzyl group in the compound (26) in the presence of anisole and an acid.
  • Step E-3 may be performed according to a method similar to that of Step B-4.
  • Method F is a method of preparing the compound (11) which is encompassed in the compound (I).
  • Step F-1 consists of
  • Step F-1A Step of removing the p-methoxybenzyl group in the compound (17) in the presence of anisole and an acid
  • Step F-1B Step of preparing the compound (If) by reacting the compound obtained in Step F-1A with an amine compound in the presence of a reduction reagent.
  • Step F-1A may be performed according to a method similar to that of Step B-4.
  • the reduction reagent to be used is not limited as long as it may be used in a reductive amination reaction of a formyl group and is preferably sodium triacetoxyborohydride or sodium borohydride.
  • the solvent to be used is preferably an ether, alcohol or a mixture thereof, and more preferably tetrahydrofuran, methanol or a mixture thereof.
  • the reaction temperature is preferably 0° C. to 60° C.
  • the reaction time is preferably 30 minutes to 14 hours.
  • a compound in which R 1 is a [N—(C 1 -C 6 alkyl)-N—(C 1 -C 6 alkyl)sulfonylamino]methyl group in the compound (I) may be prepared by reacting the compound obtained in Step F-1B with (C 1 -C 6 alkyl)sulfonyl chloride in the presence of a base.
  • the compound represented by general formula (I) or a pharmacologically acceptable salt thereof of the present invention may be administered (i) as a bulk powder per se; (ii) orally as a formulation such as a tablet, a capsule, granules, a powder or a syrup, which is prepared by mixing with a suitable pharmacologically acceptable excipient, diluent or the like; or (iii) parenterally as a formulation such as an injection or a suppository, which is prepared as described above. It is preferably orally administered.
  • formulations are prepared by well-known methods using additives such as an excipient, a binder, a disintegrator, a lubricant, an emulsifier, a stabilizer, a flavoring agent, a diluent or a solvent for injection.
  • additives such as an excipient, a binder, a disintegrator, a lubricant, an emulsifier, a stabilizer, a flavoring agent, a diluent or a solvent for injection.
  • the excipient may be, for example, an organic excipient or an inorganic excipient.
  • the organic excipient may be, for example, a sugar derivative such as lactose, sucrose, glucose, mannitol or sorbitol; a starch derivative such as corn starch; a cellulose derivative such as crystalline cellulose; gum arabic; dextran; pullulan; or the like.
  • the inorganic excipient may be, for example, a silicic acid salt derivative such as light anhydrous silicic acid, synthesized aluminum silicate; a sulfuric acid salt such as calcium sulfate; or the like.
  • the binder may be, for example, the compounds shown in the above-described excipient; gelatin; polyvinyl pyrrolidone; polyethylene glycol; or the like.
  • the disintegrator may be, for example, the compounds shown in the above-described excipient; a chemically modified starch or cellulose derivative such as sodium croscarmellose or sodium carboxymethyl starch; cross-linking polyvinyl pyrrolidone; or the like.
  • the lubricant may be, for example, talc; colloidal silica; waxes such as beeswax or sperm whale; glycol; D, L-leucine; a sulfuric acid salt such as sodium sulfate; the starch derivatives in the above-described excipient; or the like.
  • the emulsifier may be, for example, a colloidal clay such as bentonite or begum; an anionic surfactant such as lauryl sodium sulfate; a cationic surfactant such as benzalkonium chloride; a non-ionic surfactant such as polyoxyethylene alkyl ether; or the like.
  • the stabilizer may be, for example, a parahydroxybenzoic acid ester such as methyl paraben; an alcohol such as chlorobutanol; benzalkonium chloride; phenol; thimerosal; or the like.
  • the flavoring agent may be, for example, a sweetener, an acidulant, a perfume or the like, which are usually used.
  • the diluent may be, for example, water, ethanol, propylene glycol or the like.
  • the solvent for injection may be, for example, water, ethanol, glycerin or the like.
  • the dosage amount of the compound represented by general formula (I) or a pharmacologically acceptable salt thereof which is an active ingredient of the invention varies depending on symptoms, age and the like of a patient.
  • the compound represented by general formula (I) or a pharmacologically acceptable salt thereof may be administered depending on symptoms, 1 to 6 times per one day for an adult human, at 0.01 mg/kg (preferably 0.05 mg/kg) as lower limit and at 500 mg/kg (preferably 50 mg/kg) as upper limit per once when orally administered, or at 0.001 mg/kg (preferably 0.005 mg/kg) as lower limit and at 50 mg/kg (preferably 5 mg/kg) as upper limit per once when parenterally administered.
  • the compound represented by general formula (I) or a pharmacologically acceptable salt thereof of the present invention has excellent properties in terms of CETP inhibition activity, increasing action on the concentration of HDL cholesterol, decreasing action on the concentration of LDL cholesterol, rapid onset of pharmacological effect, prolonged pharmacological effect, physical stability, solubility, oral absorbability, blood concentration, cell membrane permeability, metabolic stability, tissue migration, bioavailability (BA), drug-drug interaction, toxicity or the like, and is useful as a medicament for a warm-blooded animal (particularly, for a human).
  • the above-described medicament is a medicament for treatment or prophylaxis of, preferably dyslipidemia, hypercholesterolemia, low HDL cholesterolemia, high LDL cholesterolemia, hypertriglyceridemia, arteriosclerosis, arteriosclerotic heart disease, coronary heart disease (including heart failure, myocardial infarction, angina pectoris, cardiac ischemia, cardiovascular disorder and angioplasty-related restenosis), cerebrovascular disease (including stroke and cerebral infarction), peripheral vascular disease (including diabetic vascular complications) or obesity, more preferably dyslipidemia, low HDL cholesterolemia, high LDL cholesterolemia, arteriosclerosis, arteriosclerotic heart disease or coronary heart disease, further preferably dyslipidemia, low HDL cholesterolemia, arteriosclerosis or coronary heart disease, and even more preferably low HDL cholesterolemia or arteriosclerosis.
  • dyslipidemia preferably dyslipidemia, hypercholesterolemia, low HDL cholesterolemia, high LDL cholesterolemia, hypertriglyceridemia, arteriosclerosis,
  • each of the compounds is a single enantiomer which is prepared using the intermediate compound of Reference Example 10 which is a single enantiomer.
  • the chemical structural formula in the parentheses represents the chemical structural formula of a reaction intermediate in each of the Examples or Reference Examples.
  • TBS tert-butyldimethylsilyl
  • reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate.
  • the organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • n-Heptane was added to the obtained residue and the precipitate was obtained by filtration to provide 0.93 g of the title compound as a white solid (yield: 86%).
  • reaction solution was poured into water and extracted with ethyl acetate.
  • organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate.
  • the organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate.
  • the organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate.
  • the organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • n-Hexane was added to the obtained residue and the precipitate was obtained by filtration to provide 16 mg of the title compound as a white solid (yield: 27%).
  • Methyl 5-(2-chloropyrimidin-5-yl)pentanoate which was prepared by a method similar to that of Reference Example 20, was used instead of 5-bromo-2-chloropyrimidine in the step corresponding to the first step of Example 2.
  • reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate.
  • the organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • reaction solution was poured into water and extracted with ethyl acetate.
  • organic layer was washed with 0.1 N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
  • the obtained crude product was dissolved in 2 ml of N,N-dimethylacetamide and the reaction solution was stirred at 120° C. for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure.
  • reaction solution was poured into water and extracted with ethyl acetate.
  • organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate.
  • the organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate.
  • the organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • the organic layer was separated and then the aqueous layer was extracted with toluene, and the combined organic layers were washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure and the obtained oily residue was subjected to distillation under reduced pressure (55-57° C./6 mmHg) to provide 75.3 g of the title compound as a colorless oil (yield: 57%).
  • reaction solution was filtered through Celite (trade name) and the filtrate was washed with saturated sodium hydrogencarbonate aqueous solution.
  • the obtained organic layer was washed with saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Methanol was added to the obtained residue and the precipitate was obtained by filtration to provide 20.7 g of the title compound as a white solid (yield: 87%).
  • reaction solution was stirred at room temperature for 2.3 hours. After completion of the reaction, the reaction solution was added to saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The obtained organic layer was washed with saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
  • Diastereomer 2 which was prepared by a method similar to that of Reference Example 8, in 2.5 ml of dichloromethane, 236 mg (1.05 mmol) of zinc bromide was added, and then the reaction solution was stirred at 30° C. for 68.5 hours.
  • CHIRALPAK (trade name) AD-H (0.46 cm ID ⁇ 25 cm, manufactured by Daicel Chemical Industries, Ltd.)
  • CHIRALPAK (trade name) AD-H (0.46 cm ID ⁇ 25 cm, manufactured by Daicel Chemical Industries, Ltd.)
  • reaction solution was poured into 40 ml of 0.5 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. n-Heptane was added to the obtained residue and the precipitate was obtained by filtration to provide 5.09 g of the title compound as a white solid (yield: 86%).
  • reaction solution was poured into water and extracted with ethyl acetate.
  • organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.

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